Sleep can be defined as an active, repetitive, and reversible state of perceptual disengagement from and unresponsiveness to the environment. Empirical evidence demonstrates an association between sleep and the consolidation of cognitive performance, which is required for executive functioning including abstract reasoning, goal directed behavior, and creative processing. (Carskadon M A, et al. (2005). Normal human sleep: an overview. In: Kryger M H, et al. eds. Principle and practice of sleep medicine. 4th ed. Philadelphia: Elsevier Saunders; p. 13-23; Walker M P, et al. (2002). Cognitive flexibility across the sleep wake cycle: REM-sleep enhancement of anagram problem solving. Brain Res Cogn Brain Res 2002; 14: 317-324; Curcio G, et al. (2006). Sleep loss, learning capacity, and academic performance. Sleep Med Rev, 10: 323-327.)
The sleep-related overnight brain processes are thought to influence cognitive, physical and emotional performance throughout the day due to impairment of the executive function of the prefrontal cortex. Shortness or disruption of sleep reduces necessary overnight brain activity that is needed for higher order neurocognitive functioning, and results in a decline in the ability to complete complex tasks requiring abstract thinking, creativity, integration, and planning. (Dewald J F, et al. (2010). The influence of sleep quality, sleep duration, and sleepiness on school performance in children and adolescents: A meta-analytic review. Sleep Med Rev, 14: 179-189; Dahl R E. (1996). The regulation of sleep and arousal: development and psychopathology. Dev Psychopathol 8: 3-27; Harrison Y, et al. (1998). Sleep loss impairs short and novel language tasks having a prefrontal focus. J Sleep Res, 7: 95-100.)
Sleep is clinically important for a variety of reasons. Firstly, complaints about sleep quality are common; epidemiological surveys indicate that 15-35% of the adult population complain of impaired sleep quality, such as difficulty in inducing or maintaining sleep. (Buysse D J, et al. (1988). The Pittsburgh Sleep Quality Index: A New Instrument for Psychiatric Practice and Research. Psychiatry Res, 28(2): 193-213; Karacan I, et al. (1976). Prevalence of sleep disturbances in a primarily urban Florida county. Soc Sci Med, 10: 239-244; Karacan I, et al. (1983). Sleep disturbance: A community survey. Sleep/Wake Disorders: Natural History, Epidemiology, and Long-Term Evolution. New York: Raven Press, 1983. pp. 37-60; Bixler E O, et al. (1979). Prevalence of sleep disorders in the Los Angeles Metropolitan area. Am J Psychiatry, 136: 1257-1262; Lugaresi E, et al. (1983). Good and poor sleepers: An epidemiological survey of the San Marion population. In: Guilleminault, C., and Lugaresi, E., eds. Sleep/Wake Disorders: Natural History, Epidemiology, and Long-Term Evolution. New York: Raven Press, 1983. pp. 1-12. Welstein L., et al. (1983). Insomnia in the San Francisco Bay Area: A telephone survey. Sleep/Wake Disorders: Natural History, Epidemiology, and Long-Term Evolution. New York: Raven Press, 1983. pp. 73-85; Mellinger G D, et al. (1985). Insomnia and its treatment: Prevalence and correlates. Archives Gen. Psychiatry, 42: 225-232.)
In studies conducted on rats, sustained sleep deprivation caused severe weight loss, malnutrition, and death. (Everson C A. (1993). Sustained sleep deprivation impairs host defense. Am J Physiol, 265(5 Pt 2): R1148-1154.) Impaired sleep onset, quality, and duration have been shown to have significant impacts on cognitive and behavioural functioning in adults. In adults, sustained sleep deprivation results in poor modulation of immunity, a reduction in natural immune responses and T cell cytokine production, and an adverse effect on host resistance to infectious disease. (Irwin M, et al. (1996). Partial night sleep deprivation reduces natural killer and cellular immune responses in humans. FASEB J. 10(5): 643-653.) Significant associations have also been observed between impaired sleep and hypertension (Bansil P, et al. (2011). Associations Between Sleep Disorders, Sleep Duration, Quality of Sleep, and Hypertension: Results From the National Health and Nutrition Examination Survey, 2005 to 2008. J. Clin Hypertens, 13(10): 739-743.), incidence of coronary heart disease and cardiovascular disease (Hoevenaar-Blom M P, et al. (2011). Sleep Duration and Sleep Quality in Relation to 12-Year Cardiovascular Disease Incidence: The MORGEN Study. Sleep, 34(11): 1487-1492.), and increased risk of diabetes (Knutson K L, et al. (2006). Role of Sleep Duration and Quality in the Risk and Severity of Type 2 Diabetes Mellitus. Arch Intern Med, 166(16): 1768-1774.).
Additionally, sleep is crucial for children and adolescents' learning, memory processes and school performance. Insufficient sleep, poor sleep quality and sleepiness are common problems in children and adolescents, with reported prevalence varying from 11% to 47%. These problems seriously affect learning capacity, school performance, and neuro-behavioural functioning. (Russo P M, et al. (2007). Sleep habits and circadian preference in Italian children and adolescents. J Sleep Res, 16: 163-169; Liu X, et al. (2002). Sleep duration, insomnia and behavioral problems among Chinese adolescents. Psychiatry Res, 111: 75-85. Dewald J F, et al. (2010). The influence of sleep quality, sleep duration, and sleepiness on school performance in children and adolescents: A meta-analytic review. Sleep Med Rev, 14: 179-189; Curcio G, et al. (2006). Sleep loss, learning capacity and academic performance. Sleep Med Rev, 10: 323-337; Fallone G, et al. (2002). Sleepiness in children and adolescents: clinical implications. Sleep Med Rev, 6: 287-306; Wolfson A R, et al. (2003). Understanding adolescents' sleep patterns and school performance: a critical appraisal. Sleep Med Rev, 7: 491-506.)
Gamma Aminobutyric Acid (GABA) is a primary inhibitory neurotransmitter of the central nervous system (CNS). It is well established that activation of GABA receptors favors the onset of sleep. The GABA-receptors are associated with chloride ion channels—signalling through the GABA-receptor changes the electrochemical gradient of the neutron, leading to activity inhibition (Olsen R W, Tobin A J. (1990). Molecular biology of GABAA receptors. FASEB J., 4(5): 1469-1480).
Three generations of hypnotics are based on these GABAA receptor-mediated inhibitory processes, including barbiturates, benzodiazepines, imiddazyropyridines, and cyclopyrrolones. These hypnotics decrease waking, increase slow-wave sleep and enhance the intermediate stage situated between slow-wave sleep and paradoxical sleep. (Gottesmann C. (2002). GABA mechanisms and sleep. Neuroscience, 111(2): 231-239.) For example, benzodiazepines are thought to act via interaction with the GABA receptor; enhancing the inhibitory effects of GABA. As such, Benzodiazepines are a widely used class of drugs primarily used as tranquilizers, muscle-relaxants, hypnotics, or sedatives (Valenstein M, et al. (2004). Benzodiazepine use among depressed patients treated in mental health settings. Am J Psychiatry, 161(4): 654-661). Many of these classes of drugs, however, have been found to lead to dependence and other side effects. (Rao T P, et al. (2015). In search of a safe natural sleep aid. J Am Coll Nutr, 11: 1-12.)
L-Theanine, (γ-glutamylethylamide), an amino acid naturally found abundant in tea leaves, has anxiolytic effects via the induction of a brain waves without the side effects associated with conventional sleep inducers, and has achieved significant improvements in sleep quality and efficiency relative to placebo treatments in both pediatric and adult populations, with no significant adverse effects. (Rao T P, et al. (2015). In search of a safe natural sleep aid. J Am Coll Nutr, 11: 1-12; Barrett J R, et al. (2013). To sleep or not to sleep: A systematic review of the literature of pharmacological treatments of insomnia in children and adolescents with attention-deficit/hyperactivity disorder. J Child Adol Psychop, 23.10: 640-647; Jang H S, et al. (2012). L-theanine partially counteracts caffeine-induced sleep disturbances in rats. Pharmacy Biochem Be, 101(2): 217-221; Lyon M R, et al. (2011). The effects of 1-theanine (Suntheanine®) on objective sleep quality in boys with attention deficit hyperactivity disorder (ADHD): a randomized, double-blind, placebo-controlled clinical trial. Altern Med Rev, 16(4): 348-354.)
Similarly, the side effects, tolerance, and dependency associated with benzodiazepines have led to studies of the use of Scutellaria lateriflora, or American Skullcap, to achieve anxiolytic effects. (del Mundo W F, Shepherd W C, Marose T D. 2002. Use of alternative medicine by patients in a rural family practice clinic. Fam Med, 34: 206-212; B.N.F. 2008. British National Formulary 55. BMJ Publishing Group and the RPS Publishing: London; Wolfson P, Hoffmann D L. 2003. An investigation into the efficacy of Scutellaria lateriflora in healthy volunteers. Altern Ther Health Med, 9: 74-78). Studies suggest that Scutellaria lateriflora may play a role in anxiolytic activity since its compounds are known to bind to the benzodiazepine site of the GABAA receptor (Awad R., et al. (2003). Phytochemical and biological analysis of Skullcap (Scutellaria lateriflora L.): A medicinal plant with anxiolytic properties. Phytomedicine, 10: 640-649.)
Additional studies have been conducted on the use of Rhodiola rosea L. (Rhodiola), a popular adaptogen in European and Asiatic traditional medicine. (German C, et al. (1999). Artic Root (Rhodiola rosea): the powerful ginseng alternative. Kensington Publishing Corp., New York; Spasov A A, et al. (2000). A double-blind, placebo-controlled pilot study of the stimulating and adaptogenic effect of Rhodiola rosea SHR-5 extract on the fatigue of students caused by stress during an examination period with a repeated low-dose regimen. Phytomedicine, 7(2): 85-89; Shevtsov V A, et al. (2003). A randomized trial of two different doses of a SHR-5 Rhodiola rosea extract versus placebo and control of capacity for mental work. Phytomedicine, 10(2-3): 95-105, Panossian A, Wagner H. (2005). Stimulating effect of adaptogens: an overview with particular reference to their efficacy following single dose administration. Phytother Res 19: 819-838). These studies have demonstrated pharmacological properties which include significant improvements in insomnia relative to placebo treatments without serious side effects (Darbinyan V, et al. (2007). Clinical trial of Rhodiola rosea L. extract SHR-5 in the treatment of mild to moderate depression. Nord J Psychiatry, 61: 343-348; Brown R P, Gerbarg P L, Ramazanov Z. 2002. Rhodiola rosea: a phytomedicinal overview. HerbalGram 56: 40-52.) R. rosea also possesses antistress properties due to its ability to modulate the activation of several components of the stress-response systems, such as the sympatho-adrenal system (Lishmanov Iu B, et al. (1987). Plasma beta-endorphin and stress hormones in stress and adaptation. Biull Eksp Biol Med 103(4): 422-424; Panossian A, et al. (1999). Plant adaptogens III. Earlier and more recent aspects and concepts on their mode of actions. Phytomedicine, 6: 287-300; Panossian A, Wagner H. (2005). Stimulating effect of adaptogens: an overview with particular reference to their efficacy following single dose administration. Phytother Res 19: 819-838) and the hypothalamic-pituitary-adrenal axis (Burchfield S R. (1979). The stress response: a new perspective. Psychosom Med 41(8): 661-672; Lishmanov I B, et al. (1987). Plasma beta-endorphin and stress hormones in stress and adaptation. Biull Eksp Biol Med, 103(4): 422-424; Saratikov A S, Krasnov E A (1987) Rhodiola rosea is a valuable medicinal plant (Golden Root). Tomsk State University Press, Russia; Panossian A, et al. (1999). Plant adaptogens III. Earlier and more recent aspects and concepts on their mode of actions. Phytomedicine, 6: 287-300; Panossian A, Wagner H. (2005). Stimulating effect of adaptogens: an overview with particular reference to their efficacy following single dose administration. Phytother Res 19: 819-838). Furthermore, R. rosea possesses the ability to reduce the secretion of corticotrophin-releasing factor (CRF), the major physiological mediator of stress (Lishmanov, maslova) which may have significant impacts on the reduction of insomnia and the overall improvement of sleep onset, quality, and duration.
Studies conducted on the use of Matricaria ricutita (chamomile), which also binds to GABA receptors and has been found to have benzodiazepine-like hypnotic activity (Shinomiya K, et al. (2005). Hypnotic activities of chamomile and passiflora extracts in sleep-disturbed rats. Biot Pharm Bull, 28(5): 808-810), have shown moderate effect sizes on total sleep time relative to placebo treatments in subjects with insomnia (Sarris J, et al. (2011). Herbal medicine for depression, anxiety and insomnia: A review of psychopharmacology and clinical evidence. Eur Neuropsychopharm, 21: 841-860; Zick S M, et al. (2011). Preliminary examination of the efficacy and safety of a standardized chamomile extract for chronic primary insomnia: A randomized placebo-controlled pilot study. BMC Complement Altern Med, 11:78). Other studies have achieved significant impacts on the hastening of sleep onset using Matricaria ricotta (Gould L, et al. (1973). Cardiac effect of chamomile tea. J Clin Pharmacol, 13: 475-479).
Melatonin is a hormone produced by the pineal gland from the amino acid tryptophan. Production is rhythmic in keeping with an intrinsic cycle of approximately 24 hours in duration, wherein levels are low and increase toward the nighttime (Wyatt J K, et al. (1999). Circadian temperature and melatonin rhythms, sleep, and neurobehavioral function in humans living on a 20-h day. Am J Physiol, 277(4 Pt 2): R1151-1163). Melatonin appears to have two distinct effects on the circadian clock: neuronal inhibition and phase-shifting of the sleep cycle (Liu C, et al. (1997). Molecular dissection of two distinct atoms of melatonin on the suprachiasmatic circadian clock. Neuron, 19(1): 91-102). Oral administration of supplemental melatonin during the day induces sleepiness and improves night sleep (Dollins A B, et al. (1994). Effect of inducing nocturnal serum melatonin concentrations in daytime on sleep, mood, body temperature, and performance. Proc Natl Acad Sci USA, 91(5): 1824-1828).
The existing market of sedative-hypnotics came fully into being in 1971 with flurazepam and the era of benzodiazepines (Mitler, M M. (2000). Nonselective and selective benzodiazepine receptor agonists: where are we today? Sleep, 23 (Suppl. 1): S39-S47). It has now expanded to include drugs like zolpidem (Ambien), eszopiclone (Lunesta), ramelteon (Rozerem), zaleplon (Sonata), and doxepine (Silenor), and benzodiazepines like triazolam (Halcion), temazepam (Restoril), and alprazolam (Xanax).
Studies have shown that even the novel classes of non-benzodiazepine hypnotic drugs (“Z-drugs”) lead to negative side effects, including physical effects like impaired balance (Allain H, et al. (2003). Effects on postural oscillation and memory functions of a single dose of zolpidem 5 mg, zopiclone 3.75 mg and lormetazepam 1 mg in elderly healthy subjects. A randomized, cross-over, double-blind study versus placebo. Euro J Clin Pharmacol, 59(3): 179-188; Frey D J, et al. (2011). Influence of zolpidem and sleep inertia on balance and cognition during nighttime awakening; a randomized placebo-controlled trial. J Am Geriatr Soc, 59(1): 73-81) and increased mortality (Kripke D F, et al. (2012). Hypnotics' association with mortality or cancer: a matched cohort study. BMJ Open, 2:e000850), as well as cognitive effects like impairment of task performance and severe disruption of memory (Pompeia, S., et al. (2004). Zolpidem and memory: A study using the process-dissociation procedure. Psychopharmacology, 174(3): 327-333; Huang, M P., et al. (2010). Effects of eszopiclone and zolpidem on sleep-wake behavior, anxiety-like behavior, and contextual memory in rats. Behav Brain Res, 210(1): 54-66; Stranks E K, Crowe S F. (2014). The acute cognitive effects of zopiclone, zolpidem, zaleplon, and eszopiclone: A systematic review and meta-analysis. J Clin Exp Neuropsyc, 36(7): 691-700; Allain H, et al. (2003). Effects on postural oscillation and memory functions of a single dose of zolpidem 5 mg, zopiclone 3.75 mg and lormetazepam 1 mg in elderly healthy subjects. A randomized, cross-over, double-blind study versus placebo. Euro J Clin Pharmacol, 59(3): 179-188; Frey D J, et al. (2011). Influence of zolpidem and sleep inertia on balance and cognition during nighttime awakening; a randomized placebo-controlled trial. J Am Geriatr Soc, 59(1): 73-81.), illusions and hallucinations (Stone J R, Tsuang J. (2008). Dose-related illusions and hallucinations with zaleplon. Clin Toxicol, 46: 344-345.) and addiction and dependence in as high as 47% of subjects (de las Cuevas, C. (2003). Benzodiazepines: more “behavioral” addiction than dependence. Psychopharmacology, 167(3): 297-303).
Studies have demonstrated not only strong correlations with the above side effects, but also limited effectiveness as a sleep aid. Some studies have shown that there is no potentiation of sleep by stimulation of the GABAA receptor and benzodiazepine binding sites (Mendelson, W B, Martin, J V. (1990). Effects of muscimol and flurazepam on the sleep EEG in the rat. Life Sci, 47, PL99-PL101; Lancel, M, et al. (1997). Muscimol and midazolam do not potentiate each other's effects on sleep EEG in the rat. J. Neurophysiol, 77: 1624-1629). While stimulation of the benzodiazepine binding site promotes slow-wave sleep in humans, particularly stage II (with spindle enhancement), traditional sleep aids operate at the expense of sleep stages III and IV, and inhibit paradoxical sleep and its eye movements (the deepest stage of sleep, characterized by delta waves—also known as “REM sleep”) (Gaillard, J M, et al. (1973). Effects of three benzodiazepines (nitrazepam, flunitrazepam and bromazepam) on sleep of normal subjects, studied with an automatic scoring system. Pharmakopsychiatrie, 6: 207-217; Borbely, A A, et al., (1985). Effect of benzodiazepine hypnotics on all-night sleep EEG spectra. Hum. Neurobiol., 4: 189-194; Monti, J M, Altier, H. (1973). Flunitrazepam (Ro 5-4200) and sleep cycle in normal subjects. Psycho-pharmacologia, 32: 343-349; Mendelson, W B, Martin, J V, 1990. Effects of muscimol and flurazepam on the sleep EEG in the rat. Life Sci, 47: PL99-PL101; Lancel, M, et al., (1996). Role of GABAA receptors in sleep regulation: Differential effects of muscimol and midazolam on sleep in rats. Neuropsychopharmacology, 15: 63-74.) In sum, existing sleep aids decrease waking, increase slow-wave sleep, and enhance the intermediate stage between slow-wave sleep and paradoxical sleep, but do so at the expense of paradoxical or REM sleep.
The interruption of this critical stage of sleep by traditional sleep aids is critical, as studies have shown that reduced paradoxical sleep is necessary for learning ability and memory (Fishbein W, Gutwein B M. (1977). Paradoxical sleep and memory storage processes. 19(4): 425-464; Gutwein B M, et al. (1980). Paradoxical sleep and memory: Long-term disruptive effects of anisomycin. Pharmacol Biochem Behav, 12(3): 377-384.) and brain development (Mirmiran M, Van Someren, E. (1993). The importance of REM sleep for brain maturation. J Sleep Res, 2: 188-192.)